A major problem with both Type 2 and Type 1 diabetes is that there is excessive and inappropriate production of glucose by the liver. This abnormality is the primary cause of fasting hyperglycemia and occurs in addition to defects in regulation of insulin release and in peripheral sensitivity to insulin. Therefore, agents that decrease liver glucose production would be beneficial for treating Type 2 and Type 1 diabetes.
Intensive treatment of the hyperglycemia of Type 1 diabetes mellitus has been shown to decrease the development of ocular, renal and neuropathic complications, and there is evidence that treatment is also beneficial for Type 2 diabetes. The available data also indicate that most patients with Type 2 or Type 1 diabetes are not receiving appropriate treatment. This inadequacy exists in spite of the availability of several different types of preparations of insulin as well as a number of other treatments which include agents that stimulate insulin release (e.g., sulfonylureas); influence liver glucose production (e.g., metformin); affect the sensitivity to insulin (e.g., troglitazone) and glucose absorption (e.g., α-glucosidase inhibitors). In spite of the availability of several different orally active agents that lower blood glucose levels, many patients with Type 2 diabetes also require insulin for control of their blood sugar levels. Overall, insulin usage in Type 2 diabetes exceeds that for Type 1 diabetes, and there is general agreement that there is a need for additional orally active agents to treat Type 2 diabetes and other obesity-related illnesses.
The glucocorticoid secretions of the adrenal gland (dominantly cortisol in humans) were so-named because of their ability to regulate glucose metabolism. These steroids stimulate the production of glucose in the liver by promoting gluconeogenesis, which is the biosynthesis of new glucose (i.e. not glucose from glycogen). Thus, in glucocorticoid insufficiency there is a tendency to hypoglycemia, with decreased liver glucose production. Further development of Addison's disease in the diabetic generally leads to lowered glucose levels. Conversely, glucocorticoid excess can provoke frank diabetes in individuals with latent diabetes mellitus, and generally aggravates glycemic control in established diabetics. Similar influences have been observed in various animal models.
The increased glucose production in response to glucocorticoids is due to effects on a number of proteins. Important among these are effects on various transaminases that convert amino acids to glucose precursors, and the induction of key gluconeogenic enzymes like glucose-6 phosphatase and phosphoenolpyruvate carboxy-kinase (PEPCK). Even a modest increase of PEPCK, as obtained in transgenic mice, gives rise to hyperglycemia. A genetic mouse model of Type 2 diabetes has increased levels of corticosterone (the endogenous glucocorticoid of that species) and concomitantly increased expression of PEPCK. This overexpression of PEPCK can be repressed by treatment with the GR antagonist RU-38486 with resulting in a decrease in the hyperglycemia. Other liver proteins are similarly regulated by glucocorticoids. For example, the hepatic enzyme tyrosine aminotransferase (TAT) is induced by treatment with the GR agonists prednisolone or dexamethasone; the elevated levels of this enzyme are normalized through treatment with RU-38486.
The considerations outlined above indicate that if the actions of endogenous glucocorticoids on liver glucose production could be blocked in a specific manner, glycemic control could be improved for the benefit of the diabetic patients. However, to date, all means to block glucocorticoid action have been systemic. These procedures result in undesirable side effects due to suppressed systemic glucocorticoid signaling. Thus, adrenalectomy leaves the patient with frank adrenal insufficiency and the problems of Addison's disease. Blockade of adrenal steroid production, for example by metyrapone, or of glucocorticoid action, for example with RU-38486, is ordinarily of limited duration of effectiveness; and when it is effective, it also results in generalized adrenal insufficiency. In the long term, compensatory ACTH hypersecretion and increased cortisol release eventually override the block and overcome these treatments. Elevated peripheral cortisol levels can trigger undesired side effects like hypokalemia. By contrast, a liver-specific GR antagonist would not have these problems, should counter-act the increased liver glucose production in diabetes mellitus and should be useful for treatment of Type 2 diabetes.
Previous efforts to block glucocorticoid action as a method for treating diabetes and obesity have been hampered by the fact that compounds used would generally block glucocorticoid action in all tissues and would lead to the potential problems of glucocorticoid insufficiency, such as hypotension, shock and ultimately death if the organism is exposed to sufficiently strong stress conditions. In contrast, a liver-selective GR-antagonist with minimal effects outside the liver could be used as a front line therapy for Type 2 diabetes, or could be used in conjunction with other existing therapies.
A liver selective GR antagonist offers a number of advantages. First, it would decrease liver glucose production. This action will have a significant effect on glycemic control. In fact, excessive liver glucose production can be the major defect in Type 2 diabetes. Secondly, such a drug should enhance insulin sensitivity because of the overall improvement in the metabolic milieu and the amelioration of the hyperglycemia-induced defects in insulin action and secretion. The decreased demand on β-cell secretion, as a result of a reduction in glycemia, would retard the progressive β-cell dysfunction characteristic of Type 2 diabetes. Another advantage that a liver selective GR antagonist would have compared to sulfonylurea or insulin treatment is that the patient would run a lower risk of hypoglycemia.